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September is PAD Awareness Month
We need your help to spread the word
Please help us spread the news about peripheral arterial disease. It’s easy – SVS has updated its online resources for physicians and resources for patients. Both web pages have videos, web links, scholarly articles and more, appropriate for each audience. Please share the links to people on your email list. Help us reach more patients and caregivers and spread awareness about PAD!
We need your help to spread the word
Please help us spread the news about peripheral arterial disease. It’s easy – SVS has updated its online resources for physicians and resources for patients. Both web pages have videos, web links, scholarly articles and more, appropriate for each audience. Please share the links to people on your email list. Help us reach more patients and caregivers and spread awareness about PAD!
We need your help to spread the word
Please help us spread the news about peripheral arterial disease. It’s easy – SVS has updated its online resources for physicians and resources for patients. Both web pages have videos, web links, scholarly articles and more, appropriate for each audience. Please share the links to people on your email list. Help us reach more patients and caregivers and spread awareness about PAD!
CAR T coverage: Drugmakers say no to patient reported outcomes
Drugmakers and physician groups expressed concern about connecting patient reported outcomes (PRO) to coverage decisions for chimeric antigen receptor T-cell therapy (CAR T) at a recent Medicare meeting.
Despite these objections, members of the Medicare Evidence Development and Coverage Advisory Committee (MEDCAC) generally expressed confidence in the use of PROs in a series of votes about PRO instruments’ use in cancer care trials.
MEDCAC opened a national coverage analysis in May 2018 at the request of UnitedHealthcare. The insurer had asked the Centers for Medicare & Medicaid Services to clarify the circumstances for coverage of the new CAR T therapies.
In presentations at an Aug. 22 MEDCAC meeting, representatives from the two manufacturers that have approved CAR T treatments on the market cautioned against using PROs in the context of coverage decisions, even though both companies used PRO data in their clinical trials and are collecting it in the postmarketing period.
“While Kite recognizes the importance of PROs in ... clinical trials, the PRO CAR T science, where these instruments are most appropriate for CAR T, remains a still to be determined and still is evolving and still quite early in the developments,” said William Go, MD, PhD, vice president of clinical development at Kite Pharmaceuticals, a Gilead company.
Despite PROs playing an active role in the ongoing development and clinical trials that Kite is running, in the context of CAR T, “we feel PROs are not quite ready for real-world coverage decisions at this time,” Dr. Go said.
A representative from Novartis agreed. “It is important to clearly define research objectives when considering whether to collect patient reported outcomes data, particularly given the burden associated with advanced disease experienced by the patients that are likely to receive this therapy,” Ilia Ferrusi, PhD, associate director, HEOR (CAR T Therapy), U.S. Oncology, Novartis, told the panel.
She noted that Novartis experienced challenges collecting PRO data, which resulted in risks to data quality and interpretation. “This could very well be amplified in larger trials or in real-world practice.”
The presenters’ comments were echoed by written comments submitted to the CMS prior to the MEDCAC meeting.
The American Society for Blood and Marrow Transplantation (ASBMT), despite supporting the collection of patient-reported outcomes, particularly in oncology, “strongly objects to any mechanism that would tie patient access or provider reimbursement to the reporting of PROs, especially in the case of CAR T therapy,” the organization said in a letter to the CMS.
Optimal PRO instruments and time points “are currently unknown” as the PROs used today were developed around chemotherapy use.
“Mandating the use of a current instrument or set of outcomes through NCD [national coverage determination] or CED [coverage with evidence development] will set a course of collecting data that is very likely to be inaccurate and inadequate,” they said.
The ASBMT also noted there is significant heterogeneity in the CAR T constructs and associated disease indications. “Products will utilize different scientific constructs and the time frames for clinical response and/or potential onset of toxicities may differ for each construct, which will challenge the establishment of set time points for data collection.”
And while presentations and comments focused on PROs in the context of CAR T, conversation and voting on the use of PROs was in the broader context of oncology clinical trials, not specific to CAR T, changing the nature of the debate and calling into question the point of the meeting and how it will inform the national coverage determination on CAR T specifically.
The June 15 meeting announcement published in the Federal Register stated that the advisory committee “will specifically focus on appraisal of evidence-based PRO assessments to provide information that impacts patients, their providers, and caregivers after a CAR T-cell therapy intervention for the patient’s cancer.”
However, the committee was asked to evaluate evidence on a number of potential PRO instruments in the broader context of oncology clinical trials without a cancer-specific or treatment-specific context, leading to a debate over how different types of cancer will have different kinds of PRO assessments related to them.
The CMS is expected to make a national coverage decision on CAR T-cell therapy by Feb. 16, 2019.
Drugmakers and physician groups expressed concern about connecting patient reported outcomes (PRO) to coverage decisions for chimeric antigen receptor T-cell therapy (CAR T) at a recent Medicare meeting.
Despite these objections, members of the Medicare Evidence Development and Coverage Advisory Committee (MEDCAC) generally expressed confidence in the use of PROs in a series of votes about PRO instruments’ use in cancer care trials.
MEDCAC opened a national coverage analysis in May 2018 at the request of UnitedHealthcare. The insurer had asked the Centers for Medicare & Medicaid Services to clarify the circumstances for coverage of the new CAR T therapies.
In presentations at an Aug. 22 MEDCAC meeting, representatives from the two manufacturers that have approved CAR T treatments on the market cautioned against using PROs in the context of coverage decisions, even though both companies used PRO data in their clinical trials and are collecting it in the postmarketing period.
“While Kite recognizes the importance of PROs in ... clinical trials, the PRO CAR T science, where these instruments are most appropriate for CAR T, remains a still to be determined and still is evolving and still quite early in the developments,” said William Go, MD, PhD, vice president of clinical development at Kite Pharmaceuticals, a Gilead company.
Despite PROs playing an active role in the ongoing development and clinical trials that Kite is running, in the context of CAR T, “we feel PROs are not quite ready for real-world coverage decisions at this time,” Dr. Go said.
A representative from Novartis agreed. “It is important to clearly define research objectives when considering whether to collect patient reported outcomes data, particularly given the burden associated with advanced disease experienced by the patients that are likely to receive this therapy,” Ilia Ferrusi, PhD, associate director, HEOR (CAR T Therapy), U.S. Oncology, Novartis, told the panel.
She noted that Novartis experienced challenges collecting PRO data, which resulted in risks to data quality and interpretation. “This could very well be amplified in larger trials or in real-world practice.”
The presenters’ comments were echoed by written comments submitted to the CMS prior to the MEDCAC meeting.
The American Society for Blood and Marrow Transplantation (ASBMT), despite supporting the collection of patient-reported outcomes, particularly in oncology, “strongly objects to any mechanism that would tie patient access or provider reimbursement to the reporting of PROs, especially in the case of CAR T therapy,” the organization said in a letter to the CMS.
Optimal PRO instruments and time points “are currently unknown” as the PROs used today were developed around chemotherapy use.
“Mandating the use of a current instrument or set of outcomes through NCD [national coverage determination] or CED [coverage with evidence development] will set a course of collecting data that is very likely to be inaccurate and inadequate,” they said.
The ASBMT also noted there is significant heterogeneity in the CAR T constructs and associated disease indications. “Products will utilize different scientific constructs and the time frames for clinical response and/or potential onset of toxicities may differ for each construct, which will challenge the establishment of set time points for data collection.”
And while presentations and comments focused on PROs in the context of CAR T, conversation and voting on the use of PROs was in the broader context of oncology clinical trials, not specific to CAR T, changing the nature of the debate and calling into question the point of the meeting and how it will inform the national coverage determination on CAR T specifically.
The June 15 meeting announcement published in the Federal Register stated that the advisory committee “will specifically focus on appraisal of evidence-based PRO assessments to provide information that impacts patients, their providers, and caregivers after a CAR T-cell therapy intervention for the patient’s cancer.”
However, the committee was asked to evaluate evidence on a number of potential PRO instruments in the broader context of oncology clinical trials without a cancer-specific or treatment-specific context, leading to a debate over how different types of cancer will have different kinds of PRO assessments related to them.
The CMS is expected to make a national coverage decision on CAR T-cell therapy by Feb. 16, 2019.
Drugmakers and physician groups expressed concern about connecting patient reported outcomes (PRO) to coverage decisions for chimeric antigen receptor T-cell therapy (CAR T) at a recent Medicare meeting.
Despite these objections, members of the Medicare Evidence Development and Coverage Advisory Committee (MEDCAC) generally expressed confidence in the use of PROs in a series of votes about PRO instruments’ use in cancer care trials.
MEDCAC opened a national coverage analysis in May 2018 at the request of UnitedHealthcare. The insurer had asked the Centers for Medicare & Medicaid Services to clarify the circumstances for coverage of the new CAR T therapies.
In presentations at an Aug. 22 MEDCAC meeting, representatives from the two manufacturers that have approved CAR T treatments on the market cautioned against using PROs in the context of coverage decisions, even though both companies used PRO data in their clinical trials and are collecting it in the postmarketing period.
“While Kite recognizes the importance of PROs in ... clinical trials, the PRO CAR T science, where these instruments are most appropriate for CAR T, remains a still to be determined and still is evolving and still quite early in the developments,” said William Go, MD, PhD, vice president of clinical development at Kite Pharmaceuticals, a Gilead company.
Despite PROs playing an active role in the ongoing development and clinical trials that Kite is running, in the context of CAR T, “we feel PROs are not quite ready for real-world coverage decisions at this time,” Dr. Go said.
A representative from Novartis agreed. “It is important to clearly define research objectives when considering whether to collect patient reported outcomes data, particularly given the burden associated with advanced disease experienced by the patients that are likely to receive this therapy,” Ilia Ferrusi, PhD, associate director, HEOR (CAR T Therapy), U.S. Oncology, Novartis, told the panel.
She noted that Novartis experienced challenges collecting PRO data, which resulted in risks to data quality and interpretation. “This could very well be amplified in larger trials or in real-world practice.”
The presenters’ comments were echoed by written comments submitted to the CMS prior to the MEDCAC meeting.
The American Society for Blood and Marrow Transplantation (ASBMT), despite supporting the collection of patient-reported outcomes, particularly in oncology, “strongly objects to any mechanism that would tie patient access or provider reimbursement to the reporting of PROs, especially in the case of CAR T therapy,” the organization said in a letter to the CMS.
Optimal PRO instruments and time points “are currently unknown” as the PROs used today were developed around chemotherapy use.
“Mandating the use of a current instrument or set of outcomes through NCD [national coverage determination] or CED [coverage with evidence development] will set a course of collecting data that is very likely to be inaccurate and inadequate,” they said.
The ASBMT also noted there is significant heterogeneity in the CAR T constructs and associated disease indications. “Products will utilize different scientific constructs and the time frames for clinical response and/or potential onset of toxicities may differ for each construct, which will challenge the establishment of set time points for data collection.”
And while presentations and comments focused on PROs in the context of CAR T, conversation and voting on the use of PROs was in the broader context of oncology clinical trials, not specific to CAR T, changing the nature of the debate and calling into question the point of the meeting and how it will inform the national coverage determination on CAR T specifically.
The June 15 meeting announcement published in the Federal Register stated that the advisory committee “will specifically focus on appraisal of evidence-based PRO assessments to provide information that impacts patients, their providers, and caregivers after a CAR T-cell therapy intervention for the patient’s cancer.”
However, the committee was asked to evaluate evidence on a number of potential PRO instruments in the broader context of oncology clinical trials without a cancer-specific or treatment-specific context, leading to a debate over how different types of cancer will have different kinds of PRO assessments related to them.
The CMS is expected to make a national coverage decision on CAR T-cell therapy by Feb. 16, 2019.
Does hypertensive disease of pregnancy increase future risk of CVD?
WHAT DOES THIS MEAN FOR PRACTICE?
- Patients who develop preeclampsia or gestational hypertension in their first pregnancy should be more carefully screened for subsequent development of CVD
Self-management intervention for epilepsy achieves health improvements
Self-management of epilepsy using a group-format, remote intervention improved mood, quality of life, and health functioning in high-risk individuals in a randomized, controlled trial.
In the 6-month trial, 120 individuals with epilepsy who had experienced at least one epilepsy-related health event in the previous 6 months were randomized either to a wait-list control group or a novel self‐management intervention.
The eight-session intervention, known as SMART, focused on modifiable factors that can be addressed with self-management, such as stress, substance abuse, routine, nutrition, and social support. It was delivered remotely over 8-10 weeks, either by telephone or online, after an initial in-person session.
“SMART combines the portability and low cost of a Web‐based intervention with the personally salient components of behavior modeling obtained by interacting with individuals who have ‘walked the walk’ in living with epilepsy,” Martha Sajatovic, MD, of Case Western Reserve University, Cleveland, and her coauthors wrote about their study published in Epilepsia.
Over the 6-month follow-up period, researchers found that individuals randomized to the intervention had a mean of 10.16 fewer negative health events, compared with a mean of 1.93 fewer events in the control group (P = .04).
When the authors looked at subcategories of negative health event counts – such as past 3-day seizure count or past 6‐month ED and hospitalization count – the differences were not significant. There was also no difference in seizure severity.
However, the study also showed significant improvements in participants’ self-rated depressive symptom severity, observer-rated depressive symptom severity, quality of life, and health functioning – both physical and mental – compared with controls. Intervention participants also reported significant improvements on the Epilepsy Self-Efficacy and Epilepsy Self-Management scales.
The majority of participants (94.2%) said the intervention was useful and that it covered the most important issues for them. A total of 92.3% believed the benefits of the SMART intervention were worth the hassle of taking part.
“SMART’s strengths are its foundation based on participatory research methods and an evidence‐based intervention, its use of peer educators facilitating empowerment and training, multimode delivery using traditional group format and telehealth approaches to eliminate barriers to care, and efficacy even in people who have long‐standing epilepsy,” the authors wrote.
“It is possible that SMART, which uses people with epilepsy as guides to help others learn to cope with the challenges of living with this common chronic neurologic condition, may help to alleviate some of the factors that prevent people with epilepsy from optimizing their quality of life.”
The study was supported by the Centers for Disease Control and Prevention. Three authors declared research grants, consultancies, royalties, or speaking positions with the private sector.
SOURCE: Sajatovic M et al. Epilepsia. 2018 Aug 10. doi: 10.1111/epi.14527.
Self-management of epilepsy using a group-format, remote intervention improved mood, quality of life, and health functioning in high-risk individuals in a randomized, controlled trial.
In the 6-month trial, 120 individuals with epilepsy who had experienced at least one epilepsy-related health event in the previous 6 months were randomized either to a wait-list control group or a novel self‐management intervention.
The eight-session intervention, known as SMART, focused on modifiable factors that can be addressed with self-management, such as stress, substance abuse, routine, nutrition, and social support. It was delivered remotely over 8-10 weeks, either by telephone or online, after an initial in-person session.
“SMART combines the portability and low cost of a Web‐based intervention with the personally salient components of behavior modeling obtained by interacting with individuals who have ‘walked the walk’ in living with epilepsy,” Martha Sajatovic, MD, of Case Western Reserve University, Cleveland, and her coauthors wrote about their study published in Epilepsia.
Over the 6-month follow-up period, researchers found that individuals randomized to the intervention had a mean of 10.16 fewer negative health events, compared with a mean of 1.93 fewer events in the control group (P = .04).
When the authors looked at subcategories of negative health event counts – such as past 3-day seizure count or past 6‐month ED and hospitalization count – the differences were not significant. There was also no difference in seizure severity.
However, the study also showed significant improvements in participants’ self-rated depressive symptom severity, observer-rated depressive symptom severity, quality of life, and health functioning – both physical and mental – compared with controls. Intervention participants also reported significant improvements on the Epilepsy Self-Efficacy and Epilepsy Self-Management scales.
The majority of participants (94.2%) said the intervention was useful and that it covered the most important issues for them. A total of 92.3% believed the benefits of the SMART intervention were worth the hassle of taking part.
“SMART’s strengths are its foundation based on participatory research methods and an evidence‐based intervention, its use of peer educators facilitating empowerment and training, multimode delivery using traditional group format and telehealth approaches to eliminate barriers to care, and efficacy even in people who have long‐standing epilepsy,” the authors wrote.
“It is possible that SMART, which uses people with epilepsy as guides to help others learn to cope with the challenges of living with this common chronic neurologic condition, may help to alleviate some of the factors that prevent people with epilepsy from optimizing their quality of life.”
The study was supported by the Centers for Disease Control and Prevention. Three authors declared research grants, consultancies, royalties, or speaking positions with the private sector.
SOURCE: Sajatovic M et al. Epilepsia. 2018 Aug 10. doi: 10.1111/epi.14527.
Self-management of epilepsy using a group-format, remote intervention improved mood, quality of life, and health functioning in high-risk individuals in a randomized, controlled trial.
In the 6-month trial, 120 individuals with epilepsy who had experienced at least one epilepsy-related health event in the previous 6 months were randomized either to a wait-list control group or a novel self‐management intervention.
The eight-session intervention, known as SMART, focused on modifiable factors that can be addressed with self-management, such as stress, substance abuse, routine, nutrition, and social support. It was delivered remotely over 8-10 weeks, either by telephone or online, after an initial in-person session.
“SMART combines the portability and low cost of a Web‐based intervention with the personally salient components of behavior modeling obtained by interacting with individuals who have ‘walked the walk’ in living with epilepsy,” Martha Sajatovic, MD, of Case Western Reserve University, Cleveland, and her coauthors wrote about their study published in Epilepsia.
Over the 6-month follow-up period, researchers found that individuals randomized to the intervention had a mean of 10.16 fewer negative health events, compared with a mean of 1.93 fewer events in the control group (P = .04).
When the authors looked at subcategories of negative health event counts – such as past 3-day seizure count or past 6‐month ED and hospitalization count – the differences were not significant. There was also no difference in seizure severity.
However, the study also showed significant improvements in participants’ self-rated depressive symptom severity, observer-rated depressive symptom severity, quality of life, and health functioning – both physical and mental – compared with controls. Intervention participants also reported significant improvements on the Epilepsy Self-Efficacy and Epilepsy Self-Management scales.
The majority of participants (94.2%) said the intervention was useful and that it covered the most important issues for them. A total of 92.3% believed the benefits of the SMART intervention were worth the hassle of taking part.
“SMART’s strengths are its foundation based on participatory research methods and an evidence‐based intervention, its use of peer educators facilitating empowerment and training, multimode delivery using traditional group format and telehealth approaches to eliminate barriers to care, and efficacy even in people who have long‐standing epilepsy,” the authors wrote.
“It is possible that SMART, which uses people with epilepsy as guides to help others learn to cope with the challenges of living with this common chronic neurologic condition, may help to alleviate some of the factors that prevent people with epilepsy from optimizing their quality of life.”
The study was supported by the Centers for Disease Control and Prevention. Three authors declared research grants, consultancies, royalties, or speaking positions with the private sector.
SOURCE: Sajatovic M et al. Epilepsia. 2018 Aug 10. doi: 10.1111/epi.14527.
FROM EPILEPSIA
Key clinical point:
Major finding: A remote, self-management intervention for epilepsy was associated with significantly fewer negative health events, compared with being in a wait-list control group.
Study details: A randomized, controlled trial in 120 individuals with epilepsy.
Disclosures: The study was supported by the Centers for Disease Control and Prevention. Three authors declared research grants, consultancies, royalties, or speaking positions with the private sector.
Source: Sajatovic M et al. Epilepsia. 2018 Aug 10. doi: 10.1111/epi.14527.
Emicizumab beats factor VIII prophylaxis by a wide margin
In patients with hemophilia A who do not have factor VIII inhibitors, emicizumab therapy outperformed factor VIII prophylaxis, according to a results of a randomized, open-label, phase 3 trial.
Patients treated with emicizumab had a significantly lower bleeding rate than without prophylaxis, and more than half of the treated patients had no treated bleeding events during the trial, reported lead author Johnny Mahlangu, MD, of the University of the Witwatersrand in Johannesburg, South Africa, and his colleagues.
For patients with severe hemophilia A, factor VIII infusions are standard prophylaxis for bleeding events; however, because of the short half-life of factor VIII, multiple infusions are needed each week, and bleeding events may still occur.
“Treatments with a high efficacy and reduced burden are needed,” the authors wrote in the New England Journal of Medicine.
Emicizumab may serve as such a treatment. It is a monoclonal antibody that joins activated factor IX with factor X. This combination restores hemostasis by replacing missing factor VIII. In 2017, the FDA approved emicizumab for patients with hemophilia A and anti-factor VIII alloantibodies (inhibitors).
The HAVEN 3 trial involved 152 patients with hemophilia A who did not have inhibitors. Patients were divided into four groups. The first three groups (A, B, and C) consisted of patients who had previously been receiving episodic factor VIII therapy. During the trial, group A received emicizumab 1.5 mg/kg per week, group B received emicizumab 3.0 mg/kg every 2 weeks, and group C received no prophylaxis. The fourth group (D) consisted of patients who had previously received factor VIII prophylaxis. This group received emicizumab 1.5 mg/kg per week.
Patients who received no prophylaxis had an annualized bleeding rate of 38.2 events. For patients treated with emicizumab, the annualized bleeding rates were 1.5 events for group A (96% lower than no prophylaxis; P less than .001) and 1.3 events for group B (97% lower than no prophylaxis; P less than .001).
More than half of the patients treated with emicizumab had no treated bleeding events during the trial; in comparison, all of the patients who did not receive prophylaxis had bleeding events. An intraindividual comparison of 48 patients (group D) showed that individuals treated with emicizumab had a 68% lower annualized bleeding rate than when they were receiving factor VIII prophylaxis (decrease from 4.8 events to 1.5 events; P less than .001).
The most common adverse event associated with emicizumab was injection-site reaction in 38 patients (25%). No thrombotic events, thrombotic microangiopathies, or deaths occurred.
“Although it is difficult to predict how the treatment approach will evolve, emicizumab therapy represents one option that holds promise to improve the care of patients with hemophilia A,” the researchers wrote.
The HAVEN 3 trial was funded by F. Hoffmann-La Roche and Chugai Pharmaceutical. The researchers reported support from Bayer, Baxalta, CSL Behring, and others.
SOURCE: Mahlangu et al. N Engl J Med. 2018;379:811-22.
The HAVEN 3 trial by Mahlangu et al. showed that emicizumab can significantly decrease the incidence of bleeding events in patients with hemophilia A, but questions remain about impacts on factor VIII tolerance and the role of emicizumab in long-term management, according to Margaret V. Ragni, MD.
The HAVEN 3 results showed that emicizumab was highly effective for hemophilia A patients who did not have inhibitors. In addition, thrombosis or thrombotic microangiopathy did not occur in the trial, as breakthrough bleeding was treated with factor VIII concentrate instead of prothrombin concentrate, which was used in previous trials.
“The absence of thrombosis with factor VIII concentrate is probably related to the fact that factor VIII has an affinity for binding factors IXa and X that is 10 times as high as that of emicizumab, so it displaces emicizumab, thereby avoiding potential additive toxicity,” Dr. Ragni wrote.
A survey conducted in the trial showed that patients preferred emicizumab over factor VIII, but Dr. Ragni noted that “there was no direct comparison, nor was the basis specified for the preference, such as a simpler route of administration or a reduction in the incidence of joint bleeding events or pain severity.”
Questions surrounding joint disease, efficacy for acute bleeding, and cost should be addressed before emicizumab replaces factor VIII therapy as standard of care. Additionally, the relationship between emicizumab and inhibitor immune tolerance remains unclear. One trial participant exhibited recurrence of anti-factor VIII antibody, “a finding that suggests incomplete inhibitor suppression by emicizumab prophylaxis.”
“Until more is known, it will be important for discussions between providers and patients to focus on risk, benefit, cost, and participation in observational studies and clinical trials,” Dr. Ragni wrote.
Margaret V. Ragni, MD , is with the division of hematology/oncology at the University of Pittsburgh. Dr. Ragni reported funding from Bayer, Biomarin, NovoNordisk, and others. These comments are adapted from an accompanying editorial ( N Engl J Med. 2018;379:880-2 ).
The HAVEN 3 trial by Mahlangu et al. showed that emicizumab can significantly decrease the incidence of bleeding events in patients with hemophilia A, but questions remain about impacts on factor VIII tolerance and the role of emicizumab in long-term management, according to Margaret V. Ragni, MD.
The HAVEN 3 results showed that emicizumab was highly effective for hemophilia A patients who did not have inhibitors. In addition, thrombosis or thrombotic microangiopathy did not occur in the trial, as breakthrough bleeding was treated with factor VIII concentrate instead of prothrombin concentrate, which was used in previous trials.
“The absence of thrombosis with factor VIII concentrate is probably related to the fact that factor VIII has an affinity for binding factors IXa and X that is 10 times as high as that of emicizumab, so it displaces emicizumab, thereby avoiding potential additive toxicity,” Dr. Ragni wrote.
A survey conducted in the trial showed that patients preferred emicizumab over factor VIII, but Dr. Ragni noted that “there was no direct comparison, nor was the basis specified for the preference, such as a simpler route of administration or a reduction in the incidence of joint bleeding events or pain severity.”
Questions surrounding joint disease, efficacy for acute bleeding, and cost should be addressed before emicizumab replaces factor VIII therapy as standard of care. Additionally, the relationship between emicizumab and inhibitor immune tolerance remains unclear. One trial participant exhibited recurrence of anti-factor VIII antibody, “a finding that suggests incomplete inhibitor suppression by emicizumab prophylaxis.”
“Until more is known, it will be important for discussions between providers and patients to focus on risk, benefit, cost, and participation in observational studies and clinical trials,” Dr. Ragni wrote.
Margaret V. Ragni, MD , is with the division of hematology/oncology at the University of Pittsburgh. Dr. Ragni reported funding from Bayer, Biomarin, NovoNordisk, and others. These comments are adapted from an accompanying editorial ( N Engl J Med. 2018;379:880-2 ).
The HAVEN 3 trial by Mahlangu et al. showed that emicizumab can significantly decrease the incidence of bleeding events in patients with hemophilia A, but questions remain about impacts on factor VIII tolerance and the role of emicizumab in long-term management, according to Margaret V. Ragni, MD.
The HAVEN 3 results showed that emicizumab was highly effective for hemophilia A patients who did not have inhibitors. In addition, thrombosis or thrombotic microangiopathy did not occur in the trial, as breakthrough bleeding was treated with factor VIII concentrate instead of prothrombin concentrate, which was used in previous trials.
“The absence of thrombosis with factor VIII concentrate is probably related to the fact that factor VIII has an affinity for binding factors IXa and X that is 10 times as high as that of emicizumab, so it displaces emicizumab, thereby avoiding potential additive toxicity,” Dr. Ragni wrote.
A survey conducted in the trial showed that patients preferred emicizumab over factor VIII, but Dr. Ragni noted that “there was no direct comparison, nor was the basis specified for the preference, such as a simpler route of administration or a reduction in the incidence of joint bleeding events or pain severity.”
Questions surrounding joint disease, efficacy for acute bleeding, and cost should be addressed before emicizumab replaces factor VIII therapy as standard of care. Additionally, the relationship between emicizumab and inhibitor immune tolerance remains unclear. One trial participant exhibited recurrence of anti-factor VIII antibody, “a finding that suggests incomplete inhibitor suppression by emicizumab prophylaxis.”
“Until more is known, it will be important for discussions between providers and patients to focus on risk, benefit, cost, and participation in observational studies and clinical trials,” Dr. Ragni wrote.
Margaret V. Ragni, MD , is with the division of hematology/oncology at the University of Pittsburgh. Dr. Ragni reported funding from Bayer, Biomarin, NovoNordisk, and others. These comments are adapted from an accompanying editorial ( N Engl J Med. 2018;379:880-2 ).
In patients with hemophilia A who do not have factor VIII inhibitors, emicizumab therapy outperformed factor VIII prophylaxis, according to a results of a randomized, open-label, phase 3 trial.
Patients treated with emicizumab had a significantly lower bleeding rate than without prophylaxis, and more than half of the treated patients had no treated bleeding events during the trial, reported lead author Johnny Mahlangu, MD, of the University of the Witwatersrand in Johannesburg, South Africa, and his colleagues.
For patients with severe hemophilia A, factor VIII infusions are standard prophylaxis for bleeding events; however, because of the short half-life of factor VIII, multiple infusions are needed each week, and bleeding events may still occur.
“Treatments with a high efficacy and reduced burden are needed,” the authors wrote in the New England Journal of Medicine.
Emicizumab may serve as such a treatment. It is a monoclonal antibody that joins activated factor IX with factor X. This combination restores hemostasis by replacing missing factor VIII. In 2017, the FDA approved emicizumab for patients with hemophilia A and anti-factor VIII alloantibodies (inhibitors).
The HAVEN 3 trial involved 152 patients with hemophilia A who did not have inhibitors. Patients were divided into four groups. The first three groups (A, B, and C) consisted of patients who had previously been receiving episodic factor VIII therapy. During the trial, group A received emicizumab 1.5 mg/kg per week, group B received emicizumab 3.0 mg/kg every 2 weeks, and group C received no prophylaxis. The fourth group (D) consisted of patients who had previously received factor VIII prophylaxis. This group received emicizumab 1.5 mg/kg per week.
Patients who received no prophylaxis had an annualized bleeding rate of 38.2 events. For patients treated with emicizumab, the annualized bleeding rates were 1.5 events for group A (96% lower than no prophylaxis; P less than .001) and 1.3 events for group B (97% lower than no prophylaxis; P less than .001).
More than half of the patients treated with emicizumab had no treated bleeding events during the trial; in comparison, all of the patients who did not receive prophylaxis had bleeding events. An intraindividual comparison of 48 patients (group D) showed that individuals treated with emicizumab had a 68% lower annualized bleeding rate than when they were receiving factor VIII prophylaxis (decrease from 4.8 events to 1.5 events; P less than .001).
The most common adverse event associated with emicizumab was injection-site reaction in 38 patients (25%). No thrombotic events, thrombotic microangiopathies, or deaths occurred.
“Although it is difficult to predict how the treatment approach will evolve, emicizumab therapy represents one option that holds promise to improve the care of patients with hemophilia A,” the researchers wrote.
The HAVEN 3 trial was funded by F. Hoffmann-La Roche and Chugai Pharmaceutical. The researchers reported support from Bayer, Baxalta, CSL Behring, and others.
SOURCE: Mahlangu et al. N Engl J Med. 2018;379:811-22.
In patients with hemophilia A who do not have factor VIII inhibitors, emicizumab therapy outperformed factor VIII prophylaxis, according to a results of a randomized, open-label, phase 3 trial.
Patients treated with emicizumab had a significantly lower bleeding rate than without prophylaxis, and more than half of the treated patients had no treated bleeding events during the trial, reported lead author Johnny Mahlangu, MD, of the University of the Witwatersrand in Johannesburg, South Africa, and his colleagues.
For patients with severe hemophilia A, factor VIII infusions are standard prophylaxis for bleeding events; however, because of the short half-life of factor VIII, multiple infusions are needed each week, and bleeding events may still occur.
“Treatments with a high efficacy and reduced burden are needed,” the authors wrote in the New England Journal of Medicine.
Emicizumab may serve as such a treatment. It is a monoclonal antibody that joins activated factor IX with factor X. This combination restores hemostasis by replacing missing factor VIII. In 2017, the FDA approved emicizumab for patients with hemophilia A and anti-factor VIII alloantibodies (inhibitors).
The HAVEN 3 trial involved 152 patients with hemophilia A who did not have inhibitors. Patients were divided into four groups. The first three groups (A, B, and C) consisted of patients who had previously been receiving episodic factor VIII therapy. During the trial, group A received emicizumab 1.5 mg/kg per week, group B received emicizumab 3.0 mg/kg every 2 weeks, and group C received no prophylaxis. The fourth group (D) consisted of patients who had previously received factor VIII prophylaxis. This group received emicizumab 1.5 mg/kg per week.
Patients who received no prophylaxis had an annualized bleeding rate of 38.2 events. For patients treated with emicizumab, the annualized bleeding rates were 1.5 events for group A (96% lower than no prophylaxis; P less than .001) and 1.3 events for group B (97% lower than no prophylaxis; P less than .001).
More than half of the patients treated with emicizumab had no treated bleeding events during the trial; in comparison, all of the patients who did not receive prophylaxis had bleeding events. An intraindividual comparison of 48 patients (group D) showed that individuals treated with emicizumab had a 68% lower annualized bleeding rate than when they were receiving factor VIII prophylaxis (decrease from 4.8 events to 1.5 events; P less than .001).
The most common adverse event associated with emicizumab was injection-site reaction in 38 patients (25%). No thrombotic events, thrombotic microangiopathies, or deaths occurred.
“Although it is difficult to predict how the treatment approach will evolve, emicizumab therapy represents one option that holds promise to improve the care of patients with hemophilia A,” the researchers wrote.
The HAVEN 3 trial was funded by F. Hoffmann-La Roche and Chugai Pharmaceutical. The researchers reported support from Bayer, Baxalta, CSL Behring, and others.
SOURCE: Mahlangu et al. N Engl J Med. 2018;379:811-22.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point:
Major finding: Treatment with emicizumab resulted in 68% fewer bleeding events, compared with factor VIII prophylaxis (P less than .001).
Study details: HAVEN 3 was a randomized, open-label phase 3 trial involving 152 patients who had hemophilia A without inhibitors.
Disclosures: The study was funded by F. Hoffmann-La Roche and Chugai Pharmaceutical. The authors reported support from Bayer, Baxalta, CSL Behring, and others.
Source: Mahlangu et al. N Engl J Med. 2018;379:811-22.
Nabilone May Reduce Agitation in People With Alzheimer’s Disease
The treatment also improves behavioral symptoms such as delusions, hallucinations, anxiety, and apathy.
CHICAGO—Nabilone, a synthetic cannabinoid, may effectively treat agitation in people with Alzheimer’s disease, according to a randomized, double-blind clinical trial presented at AAIC 2018.
“Agitation, including verbal or physical outbursts, general emotional distress, restlessness, and pacing, is one of the most common behavioral changes associated with Alzheimer’s disease as it progresses and can be a significant cause of caregiver stress,” said Krista L. Lanctôt, PhD, Senior Scientist at Sunnybrook Health Sciences Centre and Professor of Pharmacology and Psychiatry at the University of Toronto.
Dr. Lanctôt and colleagues investigated the potential benefits of nabilone for adults with moderate-to-severe Alzheimer’s dementia and clinically significant agitation. During the 14-week trial, 39 participants (77% male; average age, 87) received nabilone in capsule form (mean therapeutic dose, 1.6 mg) for six weeks, followed by one week without treatment and six weeks of placebo. In addition to measuring agitation, the researchers assessed overall behavioral symptoms, memory, physical changes, and safety.
Dr. Lanctôt’s group found that agitation improved significantly when participants were taking nabilone, compared with when they were receiving placebo, as measured by the Cohen-Mansfield Agitation Inventory. Nabilone also significantly improved overall behavioral symptoms, compared with placebo, as measured by the Neuropsychiatric Inventory.
In addition, the researchers observed small benefits in cognition and nutrition when participants received nabilone during the study. More people in the study experienced sedation when taking nabilone (45%) than when taking placebo (16%).
“Currently prescribed treatments for agitation in Alzheimer’s disease do not work in everybody. And when they do work, the effect is small, and they increase the risk of harmful side effects, including increased risk of death. As a result, there is an urgent need for safer medication options,” said Dr. Lanctôt. “These findings suggest that nabilone may be an effective treatment for agitation; however, the risk of sedation must be carefully monitored. A larger clinical trial would allow us to confirm our findings regarding how effective and safe nabilone is in the treatment of agitation for Alzheimer’s disease.”The FDA has not approved marijuana for the treatment or management of Alzheimer’s disease or other dementias. The use of marijuana as medical treatment is increasingly common, but much about the drug’s use in people with Alzheimer’s disease or other dementias is unknown. No robust, consistent clinical trial data support marijuana for the treatment of Alzheimer’s disease dementia or for related issues.
The treatment also improves behavioral symptoms such as delusions, hallucinations, anxiety, and apathy.
The treatment also improves behavioral symptoms such as delusions, hallucinations, anxiety, and apathy.
CHICAGO—Nabilone, a synthetic cannabinoid, may effectively treat agitation in people with Alzheimer’s disease, according to a randomized, double-blind clinical trial presented at AAIC 2018.
“Agitation, including verbal or physical outbursts, general emotional distress, restlessness, and pacing, is one of the most common behavioral changes associated with Alzheimer’s disease as it progresses and can be a significant cause of caregiver stress,” said Krista L. Lanctôt, PhD, Senior Scientist at Sunnybrook Health Sciences Centre and Professor of Pharmacology and Psychiatry at the University of Toronto.
Dr. Lanctôt and colleagues investigated the potential benefits of nabilone for adults with moderate-to-severe Alzheimer’s dementia and clinically significant agitation. During the 14-week trial, 39 participants (77% male; average age, 87) received nabilone in capsule form (mean therapeutic dose, 1.6 mg) for six weeks, followed by one week without treatment and six weeks of placebo. In addition to measuring agitation, the researchers assessed overall behavioral symptoms, memory, physical changes, and safety.
Dr. Lanctôt’s group found that agitation improved significantly when participants were taking nabilone, compared with when they were receiving placebo, as measured by the Cohen-Mansfield Agitation Inventory. Nabilone also significantly improved overall behavioral symptoms, compared with placebo, as measured by the Neuropsychiatric Inventory.
In addition, the researchers observed small benefits in cognition and nutrition when participants received nabilone during the study. More people in the study experienced sedation when taking nabilone (45%) than when taking placebo (16%).
“Currently prescribed treatments for agitation in Alzheimer’s disease do not work in everybody. And when they do work, the effect is small, and they increase the risk of harmful side effects, including increased risk of death. As a result, there is an urgent need for safer medication options,” said Dr. Lanctôt. “These findings suggest that nabilone may be an effective treatment for agitation; however, the risk of sedation must be carefully monitored. A larger clinical trial would allow us to confirm our findings regarding how effective and safe nabilone is in the treatment of agitation for Alzheimer’s disease.”The FDA has not approved marijuana for the treatment or management of Alzheimer’s disease or other dementias. The use of marijuana as medical treatment is increasingly common, but much about the drug’s use in people with Alzheimer’s disease or other dementias is unknown. No robust, consistent clinical trial data support marijuana for the treatment of Alzheimer’s disease dementia or for related issues.
CHICAGO—Nabilone, a synthetic cannabinoid, may effectively treat agitation in people with Alzheimer’s disease, according to a randomized, double-blind clinical trial presented at AAIC 2018.
“Agitation, including verbal or physical outbursts, general emotional distress, restlessness, and pacing, is one of the most common behavioral changes associated with Alzheimer’s disease as it progresses and can be a significant cause of caregiver stress,” said Krista L. Lanctôt, PhD, Senior Scientist at Sunnybrook Health Sciences Centre and Professor of Pharmacology and Psychiatry at the University of Toronto.
Dr. Lanctôt and colleagues investigated the potential benefits of nabilone for adults with moderate-to-severe Alzheimer’s dementia and clinically significant agitation. During the 14-week trial, 39 participants (77% male; average age, 87) received nabilone in capsule form (mean therapeutic dose, 1.6 mg) for six weeks, followed by one week without treatment and six weeks of placebo. In addition to measuring agitation, the researchers assessed overall behavioral symptoms, memory, physical changes, and safety.
Dr. Lanctôt’s group found that agitation improved significantly when participants were taking nabilone, compared with when they were receiving placebo, as measured by the Cohen-Mansfield Agitation Inventory. Nabilone also significantly improved overall behavioral symptoms, compared with placebo, as measured by the Neuropsychiatric Inventory.
In addition, the researchers observed small benefits in cognition and nutrition when participants received nabilone during the study. More people in the study experienced sedation when taking nabilone (45%) than when taking placebo (16%).
“Currently prescribed treatments for agitation in Alzheimer’s disease do not work in everybody. And when they do work, the effect is small, and they increase the risk of harmful side effects, including increased risk of death. As a result, there is an urgent need for safer medication options,” said Dr. Lanctôt. “These findings suggest that nabilone may be an effective treatment for agitation; however, the risk of sedation must be carefully monitored. A larger clinical trial would allow us to confirm our findings regarding how effective and safe nabilone is in the treatment of agitation for Alzheimer’s disease.”The FDA has not approved marijuana for the treatment or management of Alzheimer’s disease or other dementias. The use of marijuana as medical treatment is increasingly common, but much about the drug’s use in people with Alzheimer’s disease or other dementias is unknown. No robust, consistent clinical trial data support marijuana for the treatment of Alzheimer’s disease dementia or for related issues.
Pregnancy and Years of Reproductive Capability Are Associated With Dementia Risk
Miscarriages and age at menarche and menopause may influence the likelihood of dementia.
CHICAGO—More pregnancies and a longer span of reproductive years appear to protect women against dementia, according to a study presented at AAIC 2018. The results suggest that lifetime estrogen exposure may be an important modulator of long-term cognitive health.
The study by Paola Gilsanz, ScD, staff scientist at Kaiser Permanente in Oakland, California, and colleagues included more than 14,500 women and 50 years of follow-up data. Earlier age of menarche, later menopause, and more completed pregnancies all independently reduced the risk of dementia in women.
Reproductive Years
The researchers analyzed data from a cohort of 14,595 women in the Kaiser Permanente health care database. All of them had completed a comprehensive health checkup between 1964 and 1973 when they were ages 40 to 55. They reported their number of miscarriages, number of children, ages at first and last menstrual period, and the total number of years in their reproductive period. Most of the women in the group (68%) were white, but 16% were black, 6% Asian, and 5% Hispanic. Dr. Gilsanz looked at rates of dementia during 1996 to 2017, when the women were ages 62 to 86.
A multivariate regression model controlled for age, race, education, midlife health issues (eg, hypertension, smoking, and BMI), hysterectomy, and late-life health issues (eg, stroke, heart failure, and diabetes).
Half of the cohort had at least three children, and 75% had at least one miscarriage. The average age at menarche was 13, and the average age at last natural menstrual period was 47. This equated to an average reproductive period of 34 years.
At the end of follow-up, 36% of the cohort had developed dementia.
Women with at least three children were 12% less likely to develop dementia, compared with those with one child. The association remained significant even after researchers controlled for age, race, education, and hysterectomy.
Miscarriages also influenced the risk of dementia. Those who did not report a miscarriage were 20% less likely to develop dementia than were those who had experienced at least one miscarriage. The benefit of no miscarriage was greater among women with at least three children, conferring a 28% reduced risk.
A shorter reproductive period increased the risk of dementia. Those who experienced menarche at age 16 or older had a 31% increased risk of dementia, and those who experienced their last period at age 45 or younger had a 28% greater risk. Each additional year of reproductive capability was associated with a 2% decreased risk.
Women with between 21 and 30 reproductive years were 33% more likely to develop dementia than were those with longer reproductive periods.
Renewed Interest
“Reproductive events that signal different exposures to estrogen, like pregnancy and reproductive period, may play a role in modulating dementia risk,” Dr. Gilsanz said. “Women who are less likely to have a miscarriage may have different hormonal milieus that may be neuroprotective. Underlying health conditions increasing the risk of miscarriages may also elevate risk of dementia.”
Researchers are exploring the link between hormones and cognition with renewed interest, said Suzanne Craft, PhD, of Wake Forest University in Winston-Salem, North Carolina, who moderated a press briefing on the topic. The Women’s Heath Initiative study had a chilling effect on funding for this area of research, Dr. Craft said. “But now I think the pendulum is slowly moving back” toward supporting investigations of hormones and cognition. “It’s clear that something is going on, that there is a link. I am glad we are starting to explore this again.”
—Michele G. Sullivan
Miscarriages and age at menarche and menopause may influence the likelihood of dementia.
Miscarriages and age at menarche and menopause may influence the likelihood of dementia.
CHICAGO—More pregnancies and a longer span of reproductive years appear to protect women against dementia, according to a study presented at AAIC 2018. The results suggest that lifetime estrogen exposure may be an important modulator of long-term cognitive health.
The study by Paola Gilsanz, ScD, staff scientist at Kaiser Permanente in Oakland, California, and colleagues included more than 14,500 women and 50 years of follow-up data. Earlier age of menarche, later menopause, and more completed pregnancies all independently reduced the risk of dementia in women.
Reproductive Years
The researchers analyzed data from a cohort of 14,595 women in the Kaiser Permanente health care database. All of them had completed a comprehensive health checkup between 1964 and 1973 when they were ages 40 to 55. They reported their number of miscarriages, number of children, ages at first and last menstrual period, and the total number of years in their reproductive period. Most of the women in the group (68%) were white, but 16% were black, 6% Asian, and 5% Hispanic. Dr. Gilsanz looked at rates of dementia during 1996 to 2017, when the women were ages 62 to 86.
A multivariate regression model controlled for age, race, education, midlife health issues (eg, hypertension, smoking, and BMI), hysterectomy, and late-life health issues (eg, stroke, heart failure, and diabetes).
Half of the cohort had at least three children, and 75% had at least one miscarriage. The average age at menarche was 13, and the average age at last natural menstrual period was 47. This equated to an average reproductive period of 34 years.
At the end of follow-up, 36% of the cohort had developed dementia.
Women with at least three children were 12% less likely to develop dementia, compared with those with one child. The association remained significant even after researchers controlled for age, race, education, and hysterectomy.
Miscarriages also influenced the risk of dementia. Those who did not report a miscarriage were 20% less likely to develop dementia than were those who had experienced at least one miscarriage. The benefit of no miscarriage was greater among women with at least three children, conferring a 28% reduced risk.
A shorter reproductive period increased the risk of dementia. Those who experienced menarche at age 16 or older had a 31% increased risk of dementia, and those who experienced their last period at age 45 or younger had a 28% greater risk. Each additional year of reproductive capability was associated with a 2% decreased risk.
Women with between 21 and 30 reproductive years were 33% more likely to develop dementia than were those with longer reproductive periods.
Renewed Interest
“Reproductive events that signal different exposures to estrogen, like pregnancy and reproductive period, may play a role in modulating dementia risk,” Dr. Gilsanz said. “Women who are less likely to have a miscarriage may have different hormonal milieus that may be neuroprotective. Underlying health conditions increasing the risk of miscarriages may also elevate risk of dementia.”
Researchers are exploring the link between hormones and cognition with renewed interest, said Suzanne Craft, PhD, of Wake Forest University in Winston-Salem, North Carolina, who moderated a press briefing on the topic. The Women’s Heath Initiative study had a chilling effect on funding for this area of research, Dr. Craft said. “But now I think the pendulum is slowly moving back” toward supporting investigations of hormones and cognition. “It’s clear that something is going on, that there is a link. I am glad we are starting to explore this again.”
—Michele G. Sullivan
CHICAGO—More pregnancies and a longer span of reproductive years appear to protect women against dementia, according to a study presented at AAIC 2018. The results suggest that lifetime estrogen exposure may be an important modulator of long-term cognitive health.
The study by Paola Gilsanz, ScD, staff scientist at Kaiser Permanente in Oakland, California, and colleagues included more than 14,500 women and 50 years of follow-up data. Earlier age of menarche, later menopause, and more completed pregnancies all independently reduced the risk of dementia in women.
Reproductive Years
The researchers analyzed data from a cohort of 14,595 women in the Kaiser Permanente health care database. All of them had completed a comprehensive health checkup between 1964 and 1973 when they were ages 40 to 55. They reported their number of miscarriages, number of children, ages at first and last menstrual period, and the total number of years in their reproductive period. Most of the women in the group (68%) were white, but 16% were black, 6% Asian, and 5% Hispanic. Dr. Gilsanz looked at rates of dementia during 1996 to 2017, when the women were ages 62 to 86.
A multivariate regression model controlled for age, race, education, midlife health issues (eg, hypertension, smoking, and BMI), hysterectomy, and late-life health issues (eg, stroke, heart failure, and diabetes).
Half of the cohort had at least three children, and 75% had at least one miscarriage. The average age at menarche was 13, and the average age at last natural menstrual period was 47. This equated to an average reproductive period of 34 years.
At the end of follow-up, 36% of the cohort had developed dementia.
Women with at least three children were 12% less likely to develop dementia, compared with those with one child. The association remained significant even after researchers controlled for age, race, education, and hysterectomy.
Miscarriages also influenced the risk of dementia. Those who did not report a miscarriage were 20% less likely to develop dementia than were those who had experienced at least one miscarriage. The benefit of no miscarriage was greater among women with at least three children, conferring a 28% reduced risk.
A shorter reproductive period increased the risk of dementia. Those who experienced menarche at age 16 or older had a 31% increased risk of dementia, and those who experienced their last period at age 45 or younger had a 28% greater risk. Each additional year of reproductive capability was associated with a 2% decreased risk.
Women with between 21 and 30 reproductive years were 33% more likely to develop dementia than were those with longer reproductive periods.
Renewed Interest
“Reproductive events that signal different exposures to estrogen, like pregnancy and reproductive period, may play a role in modulating dementia risk,” Dr. Gilsanz said. “Women who are less likely to have a miscarriage may have different hormonal milieus that may be neuroprotective. Underlying health conditions increasing the risk of miscarriages may also elevate risk of dementia.”
Researchers are exploring the link between hormones and cognition with renewed interest, said Suzanne Craft, PhD, of Wake Forest University in Winston-Salem, North Carolina, who moderated a press briefing on the topic. The Women’s Heath Initiative study had a chilling effect on funding for this area of research, Dr. Craft said. “But now I think the pendulum is slowly moving back” toward supporting investigations of hormones and cognition. “It’s clear that something is going on, that there is a link. I am glad we are starting to explore this again.”
—Michele G. Sullivan
Quality and safety of hospital care from the patient perspective
Background: Delivery of high-quality, safe care is key to earning the trust and confidence of patients. Patients can be a valuable asset in determining and evaluating the quality and safety of the care they receive. Collectively analyzing patient perceptions remains a challenge.
Study design: Multicenter, wait-list design, cluster-randomized controlled trial.
Setting: Five National Health Service Trusts Hospital sites in the north of England.
Synopsis: Data were collected via validated survey of inpatients; 1,155 patient incident reports were gathered from 579 patients. Patient volunteers were trained to group these reports into 14 categories. Next, clinical researchers and physicians independently reviewed all reports for presence of a patient safety incident (PSI) using a previously determined consensus definition.
One in 10 patients identified a PSI. There was variability in classifying incidents as PSIs in some categories. Of the concerns expressed by patients, 65% were not classified as PSI. Limitations included a focus on patient’s concerns rather than safety, PSI estimates based on patient’s feedback without clinical information, and lack of inter-rater reliability estimates.
Bottom line: Effective translation of patient experience can provide valuable insights about safety and quality of care in hospital.
Citation: O’Hara JK et al. What can patients tell us about the quality and safety of hospital care? Findings from a UK multicentre survey study. BMJ Qual Saf. 2018 Mar 15. doi: 10.1136/bmjqs-2017-006974.
Dr. Chikkanna is an assistant professor in the division of hospital medicine at the University of Kentucky, Lexington.
Background: Delivery of high-quality, safe care is key to earning the trust and confidence of patients. Patients can be a valuable asset in determining and evaluating the quality and safety of the care they receive. Collectively analyzing patient perceptions remains a challenge.
Study design: Multicenter, wait-list design, cluster-randomized controlled trial.
Setting: Five National Health Service Trusts Hospital sites in the north of England.
Synopsis: Data were collected via validated survey of inpatients; 1,155 patient incident reports were gathered from 579 patients. Patient volunteers were trained to group these reports into 14 categories. Next, clinical researchers and physicians independently reviewed all reports for presence of a patient safety incident (PSI) using a previously determined consensus definition.
One in 10 patients identified a PSI. There was variability in classifying incidents as PSIs in some categories. Of the concerns expressed by patients, 65% were not classified as PSI. Limitations included a focus on patient’s concerns rather than safety, PSI estimates based on patient’s feedback without clinical information, and lack of inter-rater reliability estimates.
Bottom line: Effective translation of patient experience can provide valuable insights about safety and quality of care in hospital.
Citation: O’Hara JK et al. What can patients tell us about the quality and safety of hospital care? Findings from a UK multicentre survey study. BMJ Qual Saf. 2018 Mar 15. doi: 10.1136/bmjqs-2017-006974.
Dr. Chikkanna is an assistant professor in the division of hospital medicine at the University of Kentucky, Lexington.
Background: Delivery of high-quality, safe care is key to earning the trust and confidence of patients. Patients can be a valuable asset in determining and evaluating the quality and safety of the care they receive. Collectively analyzing patient perceptions remains a challenge.
Study design: Multicenter, wait-list design, cluster-randomized controlled trial.
Setting: Five National Health Service Trusts Hospital sites in the north of England.
Synopsis: Data were collected via validated survey of inpatients; 1,155 patient incident reports were gathered from 579 patients. Patient volunteers were trained to group these reports into 14 categories. Next, clinical researchers and physicians independently reviewed all reports for presence of a patient safety incident (PSI) using a previously determined consensus definition.
One in 10 patients identified a PSI. There was variability in classifying incidents as PSIs in some categories. Of the concerns expressed by patients, 65% were not classified as PSI. Limitations included a focus on patient’s concerns rather than safety, PSI estimates based on patient’s feedback without clinical information, and lack of inter-rater reliability estimates.
Bottom line: Effective translation of patient experience can provide valuable insights about safety and quality of care in hospital.
Citation: O’Hara JK et al. What can patients tell us about the quality and safety of hospital care? Findings from a UK multicentre survey study. BMJ Qual Saf. 2018 Mar 15. doi: 10.1136/bmjqs-2017-006974.
Dr. Chikkanna is an assistant professor in the division of hospital medicine at the University of Kentucky, Lexington.
Does BAN2401 Benefit Patients With Alzheimer’s Disease?
The study arms did not contain comparable numbers of patients who carried APOE4.
CHICAGO—BAN2401, a monoclonal antibody that targets soluble amyloid-beta oligomers, slows cognitive decline by as much as 47% and clears brain amyloid in 81% of patients with mild cognitive impairment (MCI) and very mild Alzheimer’s disease, according to the results of a phase II study presented at AAIC 2018.
Imbalanced Treatment Groups
The treatment groups were not well balanced in at least one respect, however, which could influence the interpretation of the data. APOE4-positive patients were unequally distributed through the six treatment groups, which included BAN2401 (2.5 mg/kg biweekly, 5 mg/kg monthly, 5 mg/kg biweekly, 10 mg/kg monthly, and 10 mg/kg biweekly) and placebo. This imbalance could have biased cognitive results in the antibody’s favor. APOE4 carriers represented between 70% and 80% of every unsuccessful treatment arm in the trial and approximately 29% of the arm that enjoyed significant cognitive benefits.
“This is a big confound,” said Keith Fargo, PhD, Director of Scientific Programs and Outreach at the Alzheimer’s Association. “According to the trial sponsors, … a regulatory body requested that people with the APOE4 Alzheimer’s risk gene not be included in the highest dose group for safety reasons. Because of this [request], the people in the highest-dose group are different from people in the other groups on an important dimension: they were much less likely to have the APOE4 gene, which is known to be a major risk factor for cognitive decline. So, it is plausible that the people on the highest dose declined differently due to genetic differences, rather than due to being on the highest dose. A planned subgroup analysis will shed more light on this [question] and [on] whether it reduces confidence in the overall findings.”
Regulators Influenced the Trial
Eisai, which is headquartered in Tokyo, and Biogen, which is based in Cambridge, Massachusetts, are developing the antibody. The decision to restructure the randomization was not Eisai’s, according to David Knopman, MD, a consultant in the department of neurology at Mayo Clinic in Rochester, Minnesota.
“European regulators did not allow randomization of [some] APOE4 carriers to the highest dose,” he said in an interview. “I ultimately don’t know what it would do to the results except make them even more difficult to justify as sufficient for registration. In general, in symptomatic Alzheimer’s dementia patients, APOE4 carriage has no substantial impact on rate of decline, but whether [APOE4] status interacted with the treatment is of course completely unknown. Bottom line: just another feature that makes this a phase II study that needs to be followed by a phase III study with a simple design using the high dose.”
“Regardless of who made the decision and why, the data is what it is, and the question remains,” said Michael S. Wolfe, PhD, the Mathias P. Mertes Professor of Medicinal Chemistry at the University of Kansas in Lawrence. “Given the numbers of E4-positive [patients] versus E4-negative [patients] for each treatment group, the interpretation of the results is now seriously thrown into question. The one group that showed a clear slowing of cognitive decline versus placebo—10 mg/kg biweekly—also has far fewer E4-positive [patients] versus E4-negative [patients]. This difference in proportion of E4-positive [patients] could be a major factor in the apparent reduced rate of cognitive decline and confounds the ability to tell if the 10-mg/kg biweekly dose is effective. In contrast, the 10-mg/kg monthly dose group has an E4-positive to E4-negative ratio more comparable to that of placebo, and the effect of the drug on cognitive decline under this dosing regimen is not clearly distinguishable from that seen with placebo.”
Treatment Reduced Amyloid Levels
In addition, BAN2401 failed to meet its 12-month prespecified primary cognitive end points. The investigators reached this conclusion through Bayesian analysis that strove to predict an 80% probability of achieving at least a 25% cognitive benefit. In December 2017, Eisai announced that the treatment had reached 64% probability. Because the company was optimistic about the treatment’s success, it continued with the additional six months of treatment, as the study design allowed, and reanalyzed results with a simpler and more straightforward method. This analysis concluded that the 10-mg/kg biweekly dose slowed decline on the Alzheimer’s Disease Composite Score (ADCOMS), a new tool developed and promoted by Eisai, by 30%. It also found that treatment slowed decline on the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog) by 47%. Treatment cleared brain amyloid in 81% of subjects and had positive effects on CSF biomarkers. CSF amyloid levels increased, and CSF total tau levels decreased, which indicated decreased neuronal injury.
—Michele G. Sullivan
The study arms did not contain comparable numbers of patients who carried APOE4.
The study arms did not contain comparable numbers of patients who carried APOE4.
CHICAGO—BAN2401, a monoclonal antibody that targets soluble amyloid-beta oligomers, slows cognitive decline by as much as 47% and clears brain amyloid in 81% of patients with mild cognitive impairment (MCI) and very mild Alzheimer’s disease, according to the results of a phase II study presented at AAIC 2018.
Imbalanced Treatment Groups
The treatment groups were not well balanced in at least one respect, however, which could influence the interpretation of the data. APOE4-positive patients were unequally distributed through the six treatment groups, which included BAN2401 (2.5 mg/kg biweekly, 5 mg/kg monthly, 5 mg/kg biweekly, 10 mg/kg monthly, and 10 mg/kg biweekly) and placebo. This imbalance could have biased cognitive results in the antibody’s favor. APOE4 carriers represented between 70% and 80% of every unsuccessful treatment arm in the trial and approximately 29% of the arm that enjoyed significant cognitive benefits.
“This is a big confound,” said Keith Fargo, PhD, Director of Scientific Programs and Outreach at the Alzheimer’s Association. “According to the trial sponsors, … a regulatory body requested that people with the APOE4 Alzheimer’s risk gene not be included in the highest dose group for safety reasons. Because of this [request], the people in the highest-dose group are different from people in the other groups on an important dimension: they were much less likely to have the APOE4 gene, which is known to be a major risk factor for cognitive decline. So, it is plausible that the people on the highest dose declined differently due to genetic differences, rather than due to being on the highest dose. A planned subgroup analysis will shed more light on this [question] and [on] whether it reduces confidence in the overall findings.”
Regulators Influenced the Trial
Eisai, which is headquartered in Tokyo, and Biogen, which is based in Cambridge, Massachusetts, are developing the antibody. The decision to restructure the randomization was not Eisai’s, according to David Knopman, MD, a consultant in the department of neurology at Mayo Clinic in Rochester, Minnesota.
“European regulators did not allow randomization of [some] APOE4 carriers to the highest dose,” he said in an interview. “I ultimately don’t know what it would do to the results except make them even more difficult to justify as sufficient for registration. In general, in symptomatic Alzheimer’s dementia patients, APOE4 carriage has no substantial impact on rate of decline, but whether [APOE4] status interacted with the treatment is of course completely unknown. Bottom line: just another feature that makes this a phase II study that needs to be followed by a phase III study with a simple design using the high dose.”
“Regardless of who made the decision and why, the data is what it is, and the question remains,” said Michael S. Wolfe, PhD, the Mathias P. Mertes Professor of Medicinal Chemistry at the University of Kansas in Lawrence. “Given the numbers of E4-positive [patients] versus E4-negative [patients] for each treatment group, the interpretation of the results is now seriously thrown into question. The one group that showed a clear slowing of cognitive decline versus placebo—10 mg/kg biweekly—also has far fewer E4-positive [patients] versus E4-negative [patients]. This difference in proportion of E4-positive [patients] could be a major factor in the apparent reduced rate of cognitive decline and confounds the ability to tell if the 10-mg/kg biweekly dose is effective. In contrast, the 10-mg/kg monthly dose group has an E4-positive to E4-negative ratio more comparable to that of placebo, and the effect of the drug on cognitive decline under this dosing regimen is not clearly distinguishable from that seen with placebo.”
Treatment Reduced Amyloid Levels
In addition, BAN2401 failed to meet its 12-month prespecified primary cognitive end points. The investigators reached this conclusion through Bayesian analysis that strove to predict an 80% probability of achieving at least a 25% cognitive benefit. In December 2017, Eisai announced that the treatment had reached 64% probability. Because the company was optimistic about the treatment’s success, it continued with the additional six months of treatment, as the study design allowed, and reanalyzed results with a simpler and more straightforward method. This analysis concluded that the 10-mg/kg biweekly dose slowed decline on the Alzheimer’s Disease Composite Score (ADCOMS), a new tool developed and promoted by Eisai, by 30%. It also found that treatment slowed decline on the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog) by 47%. Treatment cleared brain amyloid in 81% of subjects and had positive effects on CSF biomarkers. CSF amyloid levels increased, and CSF total tau levels decreased, which indicated decreased neuronal injury.
—Michele G. Sullivan
CHICAGO—BAN2401, a monoclonal antibody that targets soluble amyloid-beta oligomers, slows cognitive decline by as much as 47% and clears brain amyloid in 81% of patients with mild cognitive impairment (MCI) and very mild Alzheimer’s disease, according to the results of a phase II study presented at AAIC 2018.
Imbalanced Treatment Groups
The treatment groups were not well balanced in at least one respect, however, which could influence the interpretation of the data. APOE4-positive patients were unequally distributed through the six treatment groups, which included BAN2401 (2.5 mg/kg biweekly, 5 mg/kg monthly, 5 mg/kg biweekly, 10 mg/kg monthly, and 10 mg/kg biweekly) and placebo. This imbalance could have biased cognitive results in the antibody’s favor. APOE4 carriers represented between 70% and 80% of every unsuccessful treatment arm in the trial and approximately 29% of the arm that enjoyed significant cognitive benefits.
“This is a big confound,” said Keith Fargo, PhD, Director of Scientific Programs and Outreach at the Alzheimer’s Association. “According to the trial sponsors, … a regulatory body requested that people with the APOE4 Alzheimer’s risk gene not be included in the highest dose group for safety reasons. Because of this [request], the people in the highest-dose group are different from people in the other groups on an important dimension: they were much less likely to have the APOE4 gene, which is known to be a major risk factor for cognitive decline. So, it is plausible that the people on the highest dose declined differently due to genetic differences, rather than due to being on the highest dose. A planned subgroup analysis will shed more light on this [question] and [on] whether it reduces confidence in the overall findings.”
Regulators Influenced the Trial
Eisai, which is headquartered in Tokyo, and Biogen, which is based in Cambridge, Massachusetts, are developing the antibody. The decision to restructure the randomization was not Eisai’s, according to David Knopman, MD, a consultant in the department of neurology at Mayo Clinic in Rochester, Minnesota.
“European regulators did not allow randomization of [some] APOE4 carriers to the highest dose,” he said in an interview. “I ultimately don’t know what it would do to the results except make them even more difficult to justify as sufficient for registration. In general, in symptomatic Alzheimer’s dementia patients, APOE4 carriage has no substantial impact on rate of decline, but whether [APOE4] status interacted with the treatment is of course completely unknown. Bottom line: just another feature that makes this a phase II study that needs to be followed by a phase III study with a simple design using the high dose.”
“Regardless of who made the decision and why, the data is what it is, and the question remains,” said Michael S. Wolfe, PhD, the Mathias P. Mertes Professor of Medicinal Chemistry at the University of Kansas in Lawrence. “Given the numbers of E4-positive [patients] versus E4-negative [patients] for each treatment group, the interpretation of the results is now seriously thrown into question. The one group that showed a clear slowing of cognitive decline versus placebo—10 mg/kg biweekly—also has far fewer E4-positive [patients] versus E4-negative [patients]. This difference in proportion of E4-positive [patients] could be a major factor in the apparent reduced rate of cognitive decline and confounds the ability to tell if the 10-mg/kg biweekly dose is effective. In contrast, the 10-mg/kg monthly dose group has an E4-positive to E4-negative ratio more comparable to that of placebo, and the effect of the drug on cognitive decline under this dosing regimen is not clearly distinguishable from that seen with placebo.”
Treatment Reduced Amyloid Levels
In addition, BAN2401 failed to meet its 12-month prespecified primary cognitive end points. The investigators reached this conclusion through Bayesian analysis that strove to predict an 80% probability of achieving at least a 25% cognitive benefit. In December 2017, Eisai announced that the treatment had reached 64% probability. Because the company was optimistic about the treatment’s success, it continued with the additional six months of treatment, as the study design allowed, and reanalyzed results with a simpler and more straightforward method. This analysis concluded that the 10-mg/kg biweekly dose slowed decline on the Alzheimer’s Disease Composite Score (ADCOMS), a new tool developed and promoted by Eisai, by 30%. It also found that treatment slowed decline on the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog) by 47%. Treatment cleared brain amyloid in 81% of subjects and had positive effects on CSF biomarkers. CSF amyloid levels increased, and CSF total tau levels decreased, which indicated decreased neuronal injury.
—Michele G. Sullivan